1-loweralkanoyl-nipecotonitriles



United States Patent 3,551,432 1-LOWERALKANOYL-NIPECOTONITRILES NormanL. Wendler, Summit, David Taub, Metuchen,

and Chan Hwa Kuo, South Plainfield, N.J., assignors to Merck & Co.,Inc., Rahway, N.J., a corporation of New Jersey No Drawing. Originalapplication June 3, 1966, Ser. No. 554,999, now Patent No. 3,435,044.Divided and this application June 10, 1968, Ser. No. 765,713

Int. Cl. C07d 29/32 US. Cl. 260294.3 4 Claims ABSTRACT OF THE DISCLOSURENicotinonitrile is produced by reacting l-acyl-3-cyano-4-amino-1,2,5,6-tetrahydropyridine with a strong acid to produce atautomeric mixture of l-acyl-3-cyano-4-ketohexahydropyridine and1-acyl-3-cyano-4-hydroxy-1,2,5,6- tetrahydropyridines, reducing thistautomeric mixture with borohydride to produce a mixture of cis andtrans isomers of 1 acyl-3-cyano-4-hydroxyhcxahydropyridine, acylatingthese isomers to produce the corresponding 4- acyloxy derivatives, anddehydrogenating the latter derivatives with a noble metal.Alternatively, the 4-acyloxy derivative is contacted with a strong baseto produce 1- acyl-3-cyano-l,2,5,6-tetrahydropyridine which is reactedwith a noble metal to produce nicotinonitrile. Nicotinonitrile is usefulas an intermediate in the preparation of nicotinarnide.

CROSS-REFERENCE TO RELATED APPLICATION This is a division of Ser. No.554,999, filed June 3, 1966, now US. Pat. 3,435,044, issued Mar. 25,1969.

This invention relates to processes for the preparation of nicotinamide.More particularly, it is concerned with methods of preparingnicotinonitriles from 4-amino- 1,2,5,6-tetrahydropyridine and newpyridine compounds useful as intermediates in these processes.

The methods presently available for producing nicotinamide utilizevarious substituted pyridines as starting materials. These pyridines arerelatively expensive and from time to time are in short supply. Hence,other methods for producing nicotinamide utilizing other startingmaterials have been sought.

It is an object of this invention to provide methods of producingnicotinonitrile, which can be converted to nicotinamide by knownmethods, utilizing as the starting material 1 acylated derivatives of4-amino 3 cyano- 1,2,5,6-tetrahydropyridine. Another object is toprovide 1-acyl-3-cyano-4-hydroxyhexahydropyridines, the corresponding4-acyloxy derivatives, 1-acyl-3-cyano-4-ketohexahydropyridines, 1acyl-3-cyano-4-hydroxy 1,2,5,6- tetrahydropyridines, and processes ofpreparing these compounds. A further object is to provide methods forthe production of these new compounds. Other objects will be apparentfrom the detailed description hereinafter provided.

In accordance with one embodiment of this invention,

3,551,432 Patented Dec. 29, 1970 "ice it is now found thatnicotinonitrile can be prepared by the following processes:

Flowsheet 17112 )11 --oN ON A CN t t N/ R R it on on 1 Z on *CN L L N NI t l t CN A ON e n J N \N/ 1'1 wherein R represents a lower alkanoylacyl group.

In accordance with the above flow diagram, l-acyl-3-cyano-4-amino-l,2,5,6-tetrahydropyridine (1) is intimately contactedwith a strong acid in aqueous solution to produce a tautomeric mixtureof l-acyl-3-cyano-4-ketohexahydropyridine (2) and1-acyl-3-cyano-4-hydroxy- 1,2,5,6 tetrahydropyridine (3). Reduction ofthis tautomeric mixture with borohydride produces a mixture of the cisand trans isomers of 1-acyl-3-cyano-4-hydroxyhexahydropyridine (4),which is acylated to produce the corresponding 4-acyloxy derivative (5).The latter compound is then dehydrogenated with a noble metal to producenicotinoni-trile (7). Alternatively, compound (7) is intimatelycontacted with a strong base to produce 1-acyl-3-cyano-1,2,5,6-tetrahydropyridine (6), which is reacted with a noblemetal to produce the desired nicotinonitrile.

In accordance with the first step of the process of our invention, thestarting material, 1-acyl-4-arnino-3-cyano- 1,2,5,6-tetrahydropyridine,is contacted in an aqueous medium with a strong acid to producel-acyl-3-cyano-4- ketohexahydropyridine, which exists in equilibriumwith the tautomeric compound 1 acyl 3-cyano-4-hydroxy-1,2,5,6-tetrahydropyridine. Although various l-acyl compounds can beused in this step of our process, we prefer to utilize the l-loweralkanoyl derivatives such as the acetyl, l-butyryl, and l-hex-anoylderivatives since these compounds are conveniently prepared by acylationof the unacylated compound.

In carrying out this acidic rearrangement, the compound to be treated isdissolved in a dilute aqueous solution of a strong mineral acid andallowed to stand at ambient temperatures of about -50" C. and preferablyabout C. for a short period of time of from a few minutes up to aboutone hour. Among the acids which can be employed in this hydrolyticreaction are the non-oxidizing mineral acids such as hydrochloric acid,

hydrobromic acid, sulfuric acid, and phosphoric acid as well as thestrong organic acids such as trifiuoroacetic acid, i.e., having adissociation constant greater than about 1 10- and insoluble acids suchas the strongly acidic ion exchange resins. For example, ion exchangeresins which are polymers of styrene and divinylbenzene having activesites derived from organic sulfonic acids dispersed throughout thepolymer lattice are suitable for this purpose. Such strongly acidic ionexchange resins include inter alia the Dowex 50 resins of the DowChemical Company, the Amberlite IR-l20 ion exchange resin of the Rohm &Haas Company, and the Permutit Q resin of the Permutit Company.

In using the ion exchange sulfonic acid type resins, the procedureemployed is to prepare an aqueous slurry of the4-aminotetrahydropyridine compound and the ion exchange resin. Thereaction mixture is stirred, preferably at room temperature, for aperiod of from a few minutes up to one or two hours. Sufficient ionexchange resin is supplied to the reaction mixture to give a definiteacidic reaction to the aqueous slurry, i.e., so that the aqueousreaction mixture has a pH of less than about 3. The product is obtainedby separating the insoluble resin and evaporating the resulting solutionto dryness.

When reaction is effected in aqueous solution with a string acid, thereaction product is neutralized with an alkali and the product isobtained by concentrating the reaction mixture to dryness andsubsequently extracting the resulting residue with organic solvents forthe product such as methanol, toluene, benzene, and the like. Theorganic solvents are then removed by evaporation and the productcrystallized, preferably from acetone, to yield the tautomeric mixtureof the 4-keto and 4-hydroxy cornpounds.

The second step of the process of our invention comprises reducing thetautomeric mixture of 1-acyl-3-cyano- 4-ketohexahydropyridine and1-acyl-3-cyano-4-hydroxy- 1,2,5,6-tetrahydropyridine by treatment with aborohydride reducing agent to produce a mixture of the cis and transisomers of the 1-acyl-3-cyano-4-hydroxyhexahydropyridine compound.Reducing agents suitable for this purpose are alkali and alkaline earthborohydrides such as lithium, potassium, and sodium borohydride and thecalcium and magnesium borohydrides. When an excess of the borohydride isbrought into intimate contact with the1-acyl-3-cyano-4-ketohexahydropyridine for sufiicient time to completethe reaction, the corresponding 4-hydroxy compound is obtained.Following the reaction, the excess borohydride reagent is destroyed bythe addition of a solution of an acid and the product recovered byevaporating the reaction mixture to dryness under reduced pressure andextracting the residue with a suitable solvent for the product such asacetone.

The 1 acyl 3-cyano 4-hydroxyhexahydropyridine so obtained is thenacylated, preferably with a lower alkanoic acid acylating agent, toproduce the corresponding 1 acyl 4-acyloxy-3-cyanohexahydropyridine. Forexample, the product of the reduction with the borohydride can beacylated 'by reaction with a lower alkanoyl anhydride or an acid halideof a lower alkanoic acid in the presence of an acid-binding agent toproduce the corresponding 4-acyloxy compound. Thus, the cis or trans 1alkanoyloxy 4-hydroxyhexahydropyridine compound can be contacted with ananhydride of a lower alkanoic acid such as acetic acid anhydride,propionic acid anhydride, butyric acid anhydride, and the like toproduce the corresponding 4-acy1oxy compound. Alternatively, theacylation can be effected by reaction of the 4-hydroxy compound with anacid chloride or acid bromide of a lower alkanoic acid such as acetic,propionic, butyric, valeric, or hexanoic acid in the presence of anacidbinding agent such as pyridine, collidine, lutidine, and the like.The product which is formed in substantially quantitative yield isreadily obtained by evaporating the reaction mixture to dryness underreduced pressure, extracting an aqueous slurry of the resulting residuewith chloroform, and concentrating the solvent extract.

Pursuant to a further embodiment of our invention, the 1 acyl 4 acyloxy3-cyanohexahydropyridine is reacted under substantially anhydrousconditions with a strong base to produce1-acyl-3-cyano-l,2,5,6-tetrahydropyridine. The reaction is convenientlycarried out by dissolving the starting material in a solvent for thecompound, adding thereto an equivalent molar amount of a strong basesuch as an alkali or alkaline earth metal oxide, and maintaining thehexahydropyridine compound in contact with the strong base forsufficient time to complete the reaction. It is preferred to use strongbases such as alkali alkoxides, for example, alkoxides formed byreaction of alkali metals with tertiary aliphatic alcohols in effectingthis step of our process. Thus, 1-acyl-3-cyano-l,2,5,6-tetrahydropyridine is obtained by reacting 1 acyl3-cyano-4-acyloxyhexahydropyridine with potassium tertiary butoxide intertiary butanol, diluting the reaction mixture with water, extractingwith a non-polar organic solvent such as chloroform, and evaporating thechloroform extract. The product so obtained can be further purified bychromatography on neutral aluminum. Thus, 1 acetyl 3cyano-l,2,5,6-tetrahydropyridine and other l-acyl compounds wherein thel-acetyl group is replaced by a 1-propionyl, l-butyryl, l-valeryl, andl-hexanoyl substituent can be obtained in this way.

In the last step of our process, the 1-acyl-3-cyano-1,2,5,6-tetrahydropyridine or the l-acyl-4-acyloxy-3-cyanohexahydropyridineare treated by heating in contact with a noble metal catalyst to effectaromatization of the 6-membered nitrogen-containing ring to producenicotinonitrile. In accordance with this step of our invention, the1-acyl-3-cyano-1,2,5,6-tetrahydropyridine or 1-acy1-3-cyano-4-acyloxyhexahydropyridine is dehydrogenated by heating inintimate contact with a noble metal such as finely-divided palladium,platinum, ruthenium, rhodium, osmium or iridium or such a metalsupported on activated carbon at temperatures of between C. to 300 C.for a period of from 1 to 10 hours. In the preferred method ofoperation, the compound to be dehydrogenated is heated with the noblemetal in an inert solvent such as a high-boiling ether or hydrocarbonhaving a boiling point of from about 100 C. to 300 C. at a temperatureof about ZOO-250 C. for sufficient time to complete the dehydrogenation.Suitable solvents which can be used in our dehydrogenation processinclude saturated polycyclic hydrocarbons such as decalin or stilbene orhigh-boiling ethers such as diphenyl ether.

The following examples are presented to illustrate methods of carryingout the present invention.

EXAMPLE 1 1-acetyl-3-cyano-4-ketohexahydropyridine and 1-acetyl-3-cyano-4-hydroxy-l ,2,5,6-tetrahydropyridine A solution of 1 gram of1-acetyl-3-cyano-4-amino- 1,2,5,6-tetrahydropyridine in 3 ml. of 2.5 Naqueous hydrochloric acid is allowed to stand at room temperature (25C.) for approximately 10 minutes. The entire reaction mixture is thenneutralized to phenolphthalsin with aqueous 2.5 N sodium hydroxidesolution and concentrated in vacuo leaving the product as a residue. Theresidual material is flushed with methanol and toluene to removeimpurities and subsequently acidified to pH 4 with aqueous 2.5 Nhydrochloric acid, and again con- The infrared spectrum of the product,1-acetyl-3-cyano-4- keto-hexahydropyridine exhibited OH as well as C=Oabsorption at max. 3-8 and respectively indicating the presence of bothketo and enol forms. The product formed a crystalline enol acetate, M.P.74-76 C.,

OH on mail.

and an enol methyl ether derivative, M.P. 99100 C.

xCHaOH 237 mp. 11,700 and 206 m (8,850)

max.

The starting material of this example can be prepared as follows:

To a stirred slurry of 32.0 grams of 4-amino-3-cyano-1,2,5,6-tetrahydropyridine in 300 ml. of pyridine is added 150 ml. ofacetic anhydride while cooling the reaction mixture to maintain thetemperature at about 30C. During a period of about -20 minutes, thestirred material dissolved in solution gives a light yellow solution andthe product begins to precipitate. The reaction is allowed to proceedfor an additional 1 /2 hours and the precipitated product is removed byfiltration, washed successively with toluene and ether, and air dried togive substantially pure1-acetyl-4-amino-3-cyano-1,2,5,6-tetrahydropyridine, M.P. 174-177 C. Onrecrystallization of the product from acetone, the product exhibits thefollowing characteristics: M.P. 177-178" C.;

A 363 mp, (E, 11,600), Afig' 2.92, 2.99, 3.09 (HH),

EXAMPLE 2 1-acetyl-3-cyano-4-ketohexahydropyridine and 1-acetyl-3-cyano-4-hydroxy- 1,2,5 ,6-tetrahydropyridine A mixture of 10 grams of1-acetyl 3-cyano-4-amino- 1,2,5,6-tetrahydropyridine and 120 cc. of aWater slurry of Amberlite IR-120 ion exchange resin (240 mmol) and 50cc. of water is stirred at room temperature (25 C.) for about 30minutes. At the end of the stirring period the resin is removed from thereaction mixture by filtration and washed with water to remove anyoccluded product. The filtrate and resin washings are combined andconcentrated to dryness to yield the product as a residue whichcrystallizes from a mixture of acetone and ether to give a good yield ofa tautomeric mixture of 1-acetyl-3-cyano-4-hydroxyl-1,2,5,-tetrahydropyridine and 1-acetyl-3-cyan0-4-ketohexahydropyridine. M.P. 134-136 C.

EXAMPLE 3 1-acety1-3-cyano-4-hydroxypiperidine A stirred solution of 1.0gram of the tautomeric mixture of1-acetyl-3-cyano-4-ketohexahydropyridine and l-acetyl-3cyano-4-hydroxy-1,2,5,6-tetrahydropyridine in 12 ml. of water is mixedwith 300 mg. of sodium borohydride in 5 ml. of water. The progress ofthe reaction is followed by measurement of the disappearance of theultraviolet absorption. The absorption is essentially zero in about 10minutes, indicating reduction of the keto substituent at position 4 andproduction of 1-acetyl-3-cyano-4-hydroxypiperidine. The excess sodiumborohydride reagent is destroyed by the addition of 1:1 aqueous aceticacid solution and the entire neutralized reaction mixture c0ncentratedto dryness under reduced pressure, leaving a residue containing theproduct. The residue is triturated with acetone and the acetone extractconcentrated to dryness, leaving the substantially pure1-acetyl-3-cyano-4-hydroxypiperidine as a colorless oil in quantitativeyield. Thinlayer chromatography, using a mixture of chloroformmethanolin a proportion of 25:1 indicates that the product is composed of boththe cis and the trans isomers.

This procedure is repeated, utilizing as starting material the filtrateobtained in accordance with the procedure of Example 2 without isolatingthe intermediate product to obtain 1-acetyl-3-cyano-4-hydroxypiperidinein excellent yield.

x1112. 2.0 (OH), 4.48 (CN),6.12;L

EXAMPLE 4 1-acety1-3-cyano-4-acetoxypiperidine A solution of 1.0 g. of1-acetyl-3-cyano-4-hydroxypiperidine in 2 m1. of acetic anhydride and 3ml. of pyridine is maintained at 25 C. for 18 hours. The reactionmixture containing the product is concentrated to dryness, the driedresidue diluted with water, and the resulting aqueous slurry extractedwith chloroform. The chloroform extract containing the product is washedwith dilute hydrochloric acid, dilute aqueous potassium bicarbonate,sodium chloride and subsequently dried over magnesium sulfate. Theproduct, 1-acetyl-3-cyano-4-acetoxypiperidine, isobtained as a residualoil by removal of the solvent in vacuo. The product is obtained insubstantially pure form as a colorless viscous oil by moleculardistillation (B.P. -190/0.05 mm.)

0 114.41 (CN), 5.72, 8.18.2 (OAc), 6.05 1. (l l Following the aboveprocedure other l-acyl piperidine compounds such as the l-butyryl andl-hexanoyl compounds can be reacted with lower alkanoic acid anhydridesto produce the corresponding 4-acyl0xy derivatives.

EXAMPLE 5 l-acety1-3-cyano-4-acetoxy-1,2,5,6-tetrahydropyridine Asolution of 200 mg. of the tautomeric mixture of1-acetyl-3-cyano-4-ketohexahydropyridine and l-acetyl-S-cyano-4-hydroxy-1,2,5,6-pyridine in 1 ml. of acetic anhydride and 1 ml.of pyridine is maintained at 25 C. for about 18 hours. The entirereaction mixture containing the product is then concentrated to drynessin vacuo and flushed with pyridine to leave the product in solid form asa residue. The residue is crystallized from a mixture of ether andacetone. M.P. 7476 C.

xgggP 20 111/4, wer 2 2 m4, x112.

4.48 (ON), 5.65 (anol acetate) 6.07 (amide), 8.500 (enol ester) 7EXAMPLE 6 Potassium enolate of 1-acetyl-3-cyano-4-hydroxy-1,2,5,6-tetrahydropyridine N 263 mu (6, 6,000);

(:iiiido) 6.5 (enolate anion) AnaIysis.Calculated for C H N O K(percent): K, 19.14. Found (percent): K, 19.82.

EXAMPLE 7 1-acetyl-3-cyano-l ,2,5,6-tetrahydropyridine To a stirredsolution of 510 mg. of 1-acetyl-3-cyano- 4-acetoxypiperidine in 3 ml. oft-butanol under an atmosphere of nitrogen is added 2.5 ml. of 1.03 Npotassium t-butoxide in t-butanol over a period of about minutes whilemaintaining the temperature of the reaction mixture at 20 C. Thereaction mixture is diluted with water and the product,1-acetyl-3-cyano-1,2,5,6-tetrahydropyridine, extracted with chloroform.The chloroform extract is washed and dried and evaporated under reducedpressure to yield a noncrystalline residue consisting of impure product.The product is obtained in substantially pure form by chromatography ona column containing grams of neutral alumina. The product is obtained byelution of the column successively with benzene followed bybenzene-chloroform (1:1) and chloroform.

mm 212 mp. (E, 8,600), 4.49 (CN),

0 I ll Reaction of other lower alkanoic acid esters of 3-cyano-4-hydroxypiperidine with potassium tertiary butoxide by the aboveprocedure produces the corresponding l-acyl-3-cyano-1,2,5,6-tetrahydropyridine compounds.

EXAMPLE 8 Nicotinonitrile Mill... -6 (C=N), 6.10

l l' Hui...

A mixture of 1.0 gram of 1-acetyl-3-cyano-4-acetoxypiperidine, 900 mg.of 10% palladium on charcoal catalyst and 5 grams of trans stilbene ismaintained at 240 C. for 3 hours. The entire reaction mixture containingthe product is then cooled and diluted with a mixture of equal parts ofbenzene-ether and filtered, the product remaining in the filtrate. Theproduct is then extracted into 1 N aqueous hydrochloric acid solutionand the hydrochloric acid extract of the product is then made alkalineand back-extracted into chloroform. The chloroform extract is thenwashed and dried and evaporated under reduced pressure to yield theproduct in good yield as a residue. The product is obtained insubstantially pure form by sublimation of the residue to give materialhaving M.P. 4951 C.

Similarly, dehydrogenation of other lower alkanoic acid derivatives of3-cyano-4-hydroxypiperidine with palladium on charcoal in the mannerdescribed above produces nicotinonitrile.

EXAMPLE 9 Nicotinonitrile Approximately 200 mg. of1-acetyl-3-cyano-1,2,5,6- tetrahydropyridine, 190 mg. of 10% palladiumon charcoal catalyst and 2 grams of trans stilbene are maintained at atemperature of 230240 C. for a period of about 4 hours. The entirereaction mixture is cooled, diluted with a 1:1 solution of benzene andether, and the insoluble material removed by filtration from the productdissolved in the filtrate. The product is then extracted into 1 Naqueous hydrochloric acid solution and the hydrochloric acid extract ofthe product is then made alkaline and back-extracted into chloroform.The chloroform extract is then washed and dried and evaporated underreduced pressure to yield the product in good yield as a residue. Theproduct is obtained in substantially pure form by sublimation of theresidue to give nicotinonitrile, M.P. 50- 51 C.

What is claimed is:

1. A compound of the formula I It wherein R is lower alkanoyl.

2. A compound of claim 1 which is 1-acetyl-3-cyano-4-acetoxyhexahydropyridine.

3. A tautomeric mixture of l-lower alkanoyl-3-cyano-4-ketohexahydropyridine and l-lower alkanoyl-3-cyano-4-hydroxy-l,2,5,6-tetrahydropyridine.

4. A tautomeric mixture of claim 3 consisting of 1-acetyl-3-cyano-4-ketohexahydropyridine and 1 acetyl-3-cyano-4-hydroxy-l,2,5,6-tetrahydropyridine.

References Cited Bachman et al.: J. Am. Chem. Soc. 69, 1535 (1947).Gaylord: Reduction with Complex Metal Hydrides, Interscience, NY.(1956), pp. 102.

NORMA S. MILESTONE, Primary Examiner G. T. TODD, Assistant Examiner U.S.Cl. X.R. 260294.7, 294.9

